IIT CTI Bendamustine, Rituximab, Pixantrone in Relapsed/Refractory B Cell Non-Hodgkin's Lymphoma (BRP)

• ClinicalTrials.gov Identifier: NCT01491841
• Recruitment Status: Completed
• First Posted: December 14, 2011
• Results First Posted: June 14, 2019
• Last Update Posted: March 4, 2020
• Sponsor: Anne Beaven, MD
• Collaborator: CTI BioPharma
• Information provided by (Responsible Party): Anne Beaven, MD, Duke University

Tracking Information

• First Submitted Date: November 14, 2011
• First Posted Date: December 14, 2011
• Results First Submitted Date: May 22, 2017
• Results First Posted Date: June 14, 2019
• Last Update Posted Date: March 4, 2020
• Actual Study Start Date: November 1, 2011
• Actual Primary Completion Date: November 22, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 13, 2019)

Maximum Tolerated Dose [ Time Frame: 4 years ]

Dose-limiting toxicity (DLT) assessments were performed weekly during cycles 1 and 2. A DLT was defined as any grade 3 non-hematologic toxicity that lasted longer than 48 hours, despite proper supportive care, any grade 4 non-hematologic toxicity, or any grade 3 or 4 hematologic toxicity lasting longer than 7 days. Alopecia and febrile neutropenia were not considered DLTs. Any NCI CTC (National Cancer Institute Common Terminology Criteria) v4.03 grade 5 (death) toxicity was considered a DLT. Dose Limiting Toxicities were used as the assessment criteria to determine the Maximum Tolerated Dose (MTD). MTD is presented.

• Original Primary Outcome Measures (submitted: December 12, 2011): Maximum Tolerated Dose [ Time Frame: 12 months ]

Current Secondary Outcome Measures (submitted: March 13, 2019)

• Overall Response [ Time Frame: up to 220 days ]
  Partial response and complete response evaluated using a modified version of the revised response criteria for malignant lymphoma by Cheson et al Complete Response (CR) • Complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present prior to therapy. Complete Response Unconfirmed (CRu) meets the CR criteria, but with one or more of the following:

  • A residual node > 1.5 cm in greatest transverse diameter that has regressed >75% in the sum of the product of the diameters (SPD). Individual nodes that were previously confluent must have regressed >75% in their SPD compared with the size of the original mass.
  • Indeterminate bone marrow (increased number or size of aggregates without cytologic or architectural atypia by immunohistochemistry or flow cytometry).

  Partial Response (PR) • A decrease of ≥ 50% in the SPD of up to six of the largest dominant nodes or nodal masses.
• Progression Free Survival [ Time Frame: From day 1 of treatment to disease progression, death or 5 years, whichever comes first ]
• Toxicity [ Time Frame: 30 days post last dose of study drug ]
  Dose limiting toxicities plus % of patients with a clinically significant change in left ventricular ejection fraction.
• Overall Survival [ Time Frame: from day 1 of treatment to death ]

Original Secondary Outcome Measures (submitted: December 12, 2011)

• Overall Response [ Time Frame: From day 1 of treatment to best response from study drugs ]
  Partial response and complete response
• Progression Free Survival [ Time Frame: From day 1 of treatment to disease progression, death or 5 years, whichever comes first ]
• Toxicity (number of participants with adverse events) [ Time Frame: 30 days post last dose of study drug ]
  Particular attention will be paid to dose limiting toxicities and to changes in the left ventricular ejection fraction
• Overall Survival [ Time Frame: from day 1 of treatment to death ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: IIT CTI Bendamustine, Rituximab, Pixantrone in Relapsed/Refractory B Cell Non-Hodgkin's Lymphoma
• Official Title: Phase I/II Study of the Combination of Bendamustine, Rituximab and Pixantrone in Patients With Relapsed/Refractory B Cell Non-Hodgkin's Lymphoma

Brief Summary

This is a phase I trial of the combination of bendamustine, rituximab and pixantrone in patients with relapsed/refractory B cell non-Hodgkin lymphoma. A standard 3+3 design will be used to determine the maximum tolerated dose (MTD) of the combination. A static dose of bendamustine and rituximab will be used and the dose of pixantrone will be escalated in each cohort. Pixantrone will be dosed on a 21 day cycle at 55mg/m2, 85mg/m2, and 115mg/m2 in sequential cohorts dependent on acceptable toxicity profile at each dose level. MTD will be determined based on DLTs that occur during the first 2 cycles of the drug combination.

Phase II did not proceed as planned due to withdrawal of pixantrone from the US.

Detailed Description

This is a phase I trial utilizing a traditional 3+3 design to evaluate maximum tolerated dose (MTD) and optimal dose schedule of pixantrone in combination with bendamustine (120mg/m2 on day 1 of each 21 day cycle) and rituximab (375mg/m2 on day 1 of each 21 day cycle). No patients will be entered on an escalated dosage level until at least 3 patients have been treated at the previous level and assessed for a dose limiting toxicity. Dose levels will be escalated in cohorts of 3 patients as long as no drug-related DLT occurs in the first 2 cycles. If one patient is observed to suffer a DLT, this cohort will be expanded to include at least 6 patients total. If less than 2 patients in the expanded cohort of 6 patients experience a DLT, dose escalation will resume. If 2 of 6 patients enrolled at the same dose level experience a DLT, the MTD has been exceeded, and the dose escalation will cease. The next lower dose will be considered the MTD. If any patient withdraws from the study prior to completing 2 cycles for reasons other than a DLT then that patient will be replaced in order to determine the MTD.

If dose limiting toxicity is observed at the initial dose level in 2 patients, the MTD has been exceeded and the starting dose level will be reduced to 25mg/m2. If 1 patient experiences a DLT in the -1 dose range, the cohort will be expanded to at least 6 patients. If a second patient experiences a DLT at the -1 dose level, the trial will be closed.

For part 1, those who have a confirmed diagnosis of relapsed/refractory B cell non-Hodgkin's lymphoma of any subtype will be considered eligible for enrollment. Each cycle will be 21 days. Subjects will be assessed for DLTs during the first 2 cycles of study drug. They will be assessed for response after cycle 2. Patients not experiencing a DLT during the first 2 cycles and who have stable disease or better may continue to receive up to 6 cycles of treatment with the triplet combination. If any patient withdraws from the study prior to completing 2 cycles for reasons other than a DLT then that patient will be replaced in order to determine the MTD.

Phase II did not proceed as planned due to withdrawal of pixantrone from the US.

• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Dose Escalation, 3+3 design

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Non-Hodgkin's Lymphoma

Intervention

• Drug: Bendamustine + Rituximab + Pixantrone
  Dose escalation of pixantrone (55mg/m2, 85mg/m2 and 115mg/m2) in combination with static dose bendamustine (120mg/m2 on Day 1 of each 21 day) and rituximab (375mg/m2 on Day 1 of each 21 day cycle).
  Other Name: BRP; BuRP
• Drug: Pegfilgrastim
  6mg administered on Day 2 of each 21 day cycle

Study Arms

• Experimental: Phase 1: Pixantrone, 55mg/m^2
  Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 55mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle
  Interventions:

  • Drug: Bendamustine + Rituximab + Pixantrone
  • Drug: Pegfilgrastim
• Experimental: Phase 1: Pixantrone, 85mg/m^2
  Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 85mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle
  Interventions:

  • Drug: Bendamustine + Rituximab + Pixantrone
  • Drug: Pegfilgrastim
• Experimental: Phase 1: Pixantrone, 115mg/m^2
  Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 115mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle
  Interventions:

  • Drug: Bendamustine + Rituximab + Pixantrone
  • Drug: Pegfilgrastim

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 30, 2016): 33
• Original Estimated Enrollment (submitted: December 12, 2011): 36
• Actual Study Completion Date: February 17, 2017
• Actual Primary Completion Date: November 22, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Part I: Subjects must have relapsed or refractory B cell NHL;
2. Part II: Subjects must have relapsed or refractory aggressive B cell NHL including follicular lymphoma (FL) grade 3, Diffuse Large B Cell Lymphoma (DLBCL), transformed NHL, mantle cell lymphoma (MCL), or other aggressive B cell NHL histology as per the WHO 2008 criteria;
3. Refractory disease (defined as persistence of evaluable disease after therapy) or relapsed disease following at least one prior treatment regimen that should include autologous stem cell transplant unless a patient was not eligible or refused prior transplant;
4. Age ≥ 18 years old;
5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2;
6. Subjects must have measurable or evaluable disease based on physical exam and/or radiographs (CT, MRI, PET) or bone marrow involvement;
7. Female subject is either post-menopausal or surgically sterilized;

8. Laboratory Values:

   • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; lower levels accepted if due to marrow involvement by lymphoma
   • Platelets ≥ 75,000/mcl; lower levels accepted if due to marrow involvement by lymphoma
   • Total bilirubin ≤ 1.5 X institutional upper limit of normal; ≤ 3.0 ULN accepted in subjects with Gilbert's Syndrome
   • AST/ALT ≤ 1.5 X institutional upper limit of normal. Subjects with known liver involvement by lymphoma: AST/ALT ≤ 2 X institutional upper limit of normal
   • Serum creatinine < 1.5 X institutional upper limit of normal
9. Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed

Exclusion Criteria:

1. No chemotherapy, radiation, biologics or immunotherapy within 2 weeks prior to registration (6 weeks if last received BCNU or mitomycin C).
2. No radioimmunotherapy within 2 months prior to registration.
3. Subjects receiving chronic, systemic treatment with corticosteroids equivalent to > 20mg of prednisone per day. Subjects receiving replacement for adrenal insufficiency will be allowed on the study. Topical or inhaled corticosteroids are allowed.
4. Subjects with a history of another primary malignancy ≤ 3 years ago, with the exception of inactive basal, squamous cell carcinoma of the skin or superficial melanoma only requiring excision, prostate cancer with a PSA that has not increased for at least 3 months, carcinoma in situ of the cervix.
5. Major surgery ≤ 4 weeks prior to registration. Minor surgery ≤ 2 weeks prior to registration. Insertion of a vascular access device is not considered major or minor surgery. Subjects must have recovered from all surgery related toxicities to ≤ grade 1 or to baseline if subject started with > grade 1 toxicity, not otherwise violating the above inclusion criteria.
6. Subjects who have received investigational drugs ≤ 4 weeks prior to registration.

7. Impaired Cardiac Function:

   • QTc > 480 on screening ECG.
   • Previous history of angina pectoris or acute MI within 6 months
   • Congestive heart failure (New York Heart Association functional classification III-IV) or baseline MUGA/ECHO shows estimated LVEF < 45%
   • Any history of torsade de pointes, ventricular fibrillation, uncontrolled ventricular tachycardia, or uncontrolled atrial fibrillation.
8. Female patients who are pregnant or breastfeeding
9. Patients with history of untreated hepatitis B or who are known carriers of hepatitis B will be excluded from this trial. All subjects will be screened prior to study entry.
10. Concurrent use of other anti-cancer agents or anti-cancer treatments.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01491841
• Other Study ID Numbers: Pro00030834
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Anne Beaven, MD, Duke University
• Study Sponsor: Anne Beaven, MD
• Collaborators: CTI BioPharma

Investigators

• Principal Investigator: David Rizzieri, MD; Duke University

• PRS Account: Duke University
• Verification Date: March 2020